Identification of melanin concentrating hormone (MCH) as the natural ligand for the orphan somatostatin‐like receptor 1 (SLC‐1)

Abstract

To identify possible ligands of the orphan somatostatin‐like receptor 1 (SLC‐1), rat brain extracts were analyzed by using the functional expression system of Xenopus oocytes injected with cRNAs encoding SLC‐1 and G protein‐gated inwardly rectifying potassium channels (GIRK). A strong inward current was observed with crude rat brain extracts which upon further purification by cation exchange chromatography and high performance liquid chromatography (HPLC) yielded two peptides with a high agonist activity. Mass spectrometry and partial peptide sequencing revealed that one peptide is identical with the neuropeptide melanin concentrating hormone (MCH), the other represents a truncated version of MCH lacking the three N‐terminal amino acid residues. Xenopus oocytes expressing the MCH receptor responded to nM concentrations of synthetic MCH not only by the activation of GIRK‐mediated currents but also by the induction of Ca²⁺ dependent chloride currents mediated by phospholipase C. This indicates that the MCH receptor can couple either to the G_i‐ or G_q‐mediated signal transduction pathway, suggesting that MCH may serve for a number of distinct brain functions including food uptake behavior.